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PDBsum entry 1kf9
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Hormone/growth factor
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PDB id
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1kf9
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Contents |
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160 a.a.
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193 a.a.
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175 a.a.
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure of a phage display-Derived variant of human growth hormone complexed to two copies of the extracellular domain of its receptor: evidence for strong structural coupling between receptor binding sites.
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Authors
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C.Schiffer,
M.Ultsch,
S.Walsh,
W.Somers,
A.M.De vos,
A.Kossiakoff.
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Ref.
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J Mol Biol, 2002,
316,
277-289.
[DOI no: ]
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PubMed id
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Abstract
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The structure of the ternary complex between the phage display- optimized,
high-affinity Site 1 variant of human growth hormone (hGH) and two copies of the
extracellular domain (ECD) of the hGH receptor (hGHR) has been determined at 2.6
A resolution. There are widespread and significant structural differences
compared to the wild-type ternary hGH hGHR complex. The hGH variant (hGH(v))
contains 15 Site 1 mutations and binds>10(2) tighter to the hGHR ECD (hGH(R1))
at Site 1. It is biologically active and specific to hGHR. The hGH(v) Site 1
interface is somewhat smaller and 20% more hydrophobic compared to the wild-type
(wt) counterpart. Of the ten hormone-receptor H-bonds in the site, only one is
the same as in the wt complex. Additionally, several regions of hGH(v) structure
move up to 9A in forming the interface. The contacts between the C-terminal
domains of two receptor ECDs (hGH(R1)- hGH(R2)) are conserved; however, the
large changes in Site 1 appear to cause global changes in the domains of hGH(R1)
that affect the hGH(v)-hGH(R2) interface indirectly. This coupling is manifested
by large changes in the conformation of groups participating in the Site 2
interaction and results in a structure for the site that is reorganized
extensively. The hGH(v)- hGH(R2) interface contains seven H-bonds, only one of
which is found in the wt complex. Several groups on hGH(v) and hGH(R2) undergo
conformational changes of up to 8 A. Asp116 of hGH(v) plays a central role in
the reorganization of Site 2 by forming two new H-bonds to the side-chains of
Trp104(R2) and Trp169(R2), which are the key binding determinants of the
receptor. The fact that a different binding solution is possible for Site 2,
where there were no mutations or binding selection pressures, indicates that the
structural elements found in these molecules possess an inherent functional
plasticity that enables them to bind to a wide variety of binding surfaces.
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Figure 5.
Figure 5. Conformational changes in mini-helix residues
(42, 45, 46) comparing the free hGH[v] molecule (top) and the
bound hGH[v] to hGH[R1] (bottom). H-bonding interactions with
receptor groups are shown for the bound form.
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Figure 7.
Figure 7. Stereo drawing comparing the region around
Trp169[R2] in Site 2. The wt complex residues are colored in
green (top). The hGH[v] complex residues are shown in yellow
(bottom). Hormone residues are labeled in black and receptor
residues in red. Arrows point to the carbonyl oxygen atom of the
peptide bond (169) that flips the conformation of the Trp169[R2]
side-chain.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2002,
316,
277-289)
copyright 2002.
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